NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance<sup>1,2</sup>. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)<sup>3-5</sup>. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase<sup>6</sup>. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice<sup>7</sup> that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.

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Publication Details

Journal
Nature
Published
2025-11-26
DOI
https://doi.org/10.1038/s41586-025-09727-z
Citations
2
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
3.04
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article

NSD2 targeting reverses plasticity and drug resistance in prostate cancer

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2 citations
Nature
Prostate Cancer Treatment and Research
3.04
article

NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Fabio Socciarelli, Michael M. Shen, Ziv Frankenstein, Cory Abate‐Shen, Kristjan H. Gretarsson, Charles L. Sawyers, Mark A. Rubin, Jia J. Li, Andrea Califano, Himisha Beltran, Ouathek Ouerfelli, Hanyang Dong, Tania Pannellini, Brian D. Robinson, Wei Yuan, Kevin Gardner, Or Gozani, Massimo Loda, Johann Sebastian De Bono, Alessandro Vasciaveo, Min Zou, Chao Lü, Zhen Sun, Dimitris Karagiannis, Xiaohong Chen, Yu Chen, Guangli Yang, Gabriel Marchese Aizenman, Xinjing Xu
article en
2 citations

Abstract

Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance<sup>1,2</sup>. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)<sup>3-5</sup>. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase<sup>6</sup>. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice<sup>7</sup> that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.

NatureVol. 649(8095)
University of Bern (CH), Bern University of Applied Sciences (CH), Memorial Sloan Kettering Cancer Center (US), Howard Hughes Medical Institute (US), Harvard University (US), Institute of Cancer Research (GB), Shandong University (CN), Sanford Burnham Prebys Medical Discovery Institute (US), Cornell University (US), Discovery Institute (US), University of Oxford (GB), Dana-Farber Cancer Institute (US), Chan Zuckerberg Initiative (United States) (US), Arvinas (United States) (US), European Institute of Oncology (IT), Columbia University (US), Stanford University (US)
Openalex Percentile: Top 7%
Prostate Cancer Treatment and Research
3.04
DOIOpen Access PDFOpenAlex
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